Our program project consists of 5 projects and two cores focusing on anti- neutrophil cytoplasmic autoantibody (ANCA) necrotizing and crescentic glomerulonephritis (GN) and small vessel vasculitis (SVV). The scope of the investigation and the diversity of the investigators allow for an integrated evaluation of basic molecular and clinical immunological and epidemiological studies pertaining to both anti-myeloperoxidase (MPO) and proteinase 3 (PR3) autoimmune response. Project 1 considers the derivation of murine anti-MPO autoantibodies with respect to relative contributions of antibody heavy and light chains and somatic mutations within them using basic molecular immunologic techniques and transgenic mice. In parallel, Project 2 investigates the human ANCA autoimmune response with respect to the contribution of light and heavy chains and somatic mutations within them, and the fine specificity of specific epitopes responsible for the generation of ANCA during disease onset or relapse. A novel paradigm of autoimmune response with respect to the contribution of light and heavy chains and somatic mutations within them, and the fine specificity of specific epitopes considered; that is, that the ANCA immune response is directed not only to MPO or PR3, but also to peptides complimentary in translation to MPO or PR3. Project 3 tests the hypothesis that ANCA directly participate in the pathogenesis of the ANCA immune response, determines the mechanism by which ANCA activate neutrophils and monocytes, delineates the mechanism by which the ANCA antigens MPO and PR3 directly induce vascular damage. Project 4 studies in vitro development of ANCA GN using animal models in which circulating anti-myeloperoxidase antibodies conspire to produce to GN. Project 5 uses state of t he art epidemiological techniques in a large population of ANCA GN patients to ascertain those environmental factors that predispose to the development and exacerbation of the ANCA immune response. In particular the role of silica exposure in the induction of ANCA GN will be tested in animal studies as well as in man. These investigations are tightly interwoven using state of the art techniques. Together, these sharpy focused and integrated projects will shed light on the central question of the overall project. What causes ANCA GN? If we knew the causes of this most aggressive form of glomerular injury targeted therapy would be in the offing. The program involves investigators from the Department of Medicine, Pathology, Microbiology and Immunology in the School of Medicine, the Department of Epidemiology in the School of Public Health, the Department of Medicinal Chemistry in the School of Pharmacy, and the National Institute of Environmental Health Sciences.